Factors influencing the recovery from potentially lethal damage (PLD) in mammalian cells in vitro and in vivo

Bertrand, M; Deen, Dennis F.

doi:10.1016/s0305-7372(80)80022-3

Cited by 16 publications

(5 citation statements)

References 67 publications

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“…The addition of nutrient-rich medium did not appear to release the populations from plateau-phase since there was no detectable increase in the number of cells recovered from the monolayers during the post-irradiation period. This modified procedure has also been used to study repair (Bertrand, 1980) Fraction number (Bright) Figure 5 Survival of KHT cells stained in vivo and irradiated in vitro. KHT cells growing as intramuscular tumours were stained in vivo after i.v.…”

Section: Resultsmentioning

confidence: 99%

Radiation sensitivity of tumour cells stained in vitro or in vivo with the bisbenzimide fluorochrome Hoechst 33342

Young

Hill²

1989

Br J Cancer

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Summary The DNA-binding bisbenzimide fluorochrome Hoechst 33342 is being used routinely in radiobiological studies to assess cell kinetic parameters and tumour blood flow. However, there are reports in the literature which indicate that exposure to this compound can affect the radiation sensitivity of tumour cell populations. In this investigation, it was found that staining murine tumour cells in vitro with H33342 at concentrations >0.1 gLM before irradiation resulted in radioprotection. The protection factor calculated for fibrosarcoma cells stained with 10 IM H33342 was 1.7. Varying the time between radiation treatment and exposure to the fluorochrome demonstrated that the effect rapidly changed to radiosensitisation when staining was performed subsequent to irradiation. Cells in transplanted KHT tumours were stained in vivo by intravenous administration of H33342 to determine whether the radiation sensitivity of these populations might also be modified. Flow cytometric analysis of suspensions prepared from tumours stained in this manner revealed that recovered cells exhibited a >100-fold range in fluorescence intensities. These suspensions were irradiated in vitro and the cells were then fractionated according to fluorochrome content using cell sorting.Little evidence for a radioprotective effect was observed when these subpopulations were assessed for survival, even when tumour-bearing mice were given doses of H33342 which approached the LD50. Further analysis demonstrated that insufficient amounts of the fluorochrome were taken up by cells during in vivo staining to attain levels required for radioprotection. However, our results indicate that the amount of H33342 accumulated by cells may affect the radiation sensitivity of populations exposed to high concentrations of this fluorochrome, such as those required to achieve stoichiometric binding to DNA.

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Section: Resultsmentioning

confidence: 99%

Radiation sensitivity of tumour cells stained in vitro or in vivo with the bisbenzimide fluorochrome Hoechst 33342

Young

Hill²

1989

Br J Cancer

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“…Neither the lesions nor the biochemical repair processes involved in the repair of potentially lethal damage have yet been fully elucidated; moreover, the relationship between repair of potentially lethal damage and repair of sublethal damage remains unclear (Iliakis 1988, Nelson et al 1990. Although most studies of sublethal and potentially lethal damage repair have used ionizing radiation or UV-radiation, there have been some studies using anticancer drugs (Ray et al 1973, Barranco, Novak & Humphrey 1975, Hahn 1975, Bertrand & Deen 1980. Potentially lethal damage repair has been observed for the monofunctional alkylating agent methyl methane sulfonate, the bifunctional alkylating agent nitrogen mustard, and for 5-fluorouracil, bleomycin, and mechlorethamine.…”

Section: Discussionmentioning

confidence: 99%

Effects of mitomycin C and porfiromycin on exponentially growing and plateau phase cultures

Rockwell¹,

Hughes²

1994

Cell Proliferation

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Laboratory studies and clinical trials are exploring the use of hypoxia-directed cytotoxic agents as adjuncts to radiotherapy. Because hypoxia and the microenvironmental inadequacies associated with hypoxia in solid tumours inhibit cell proliferation, an essential requirement for the successful use of hypoxia-directed drugs in cancer therapy is that these drugs be toxic to quiescent tumour cells, as well as tumour cells progressing rapidly through the cell cycle. The experiments reported here compared the cytotoxicities of mitomycin C and porfiromycin to exponentially growing and plateau phase cultures of EMT6 mouse mammary tumour cells. The proliferative status of the cultures did not influence the cytotoxicity of mitomycin C under either aerobic or hypoxic conditions, or the cytotoxicity of porfiromycin in air. Exponentially growing cultures were slightly more sensitive than plateau phase cultures to porfiromycin in hypoxia, but the difference between the sensitivities of proliferating and quiescent cells was much smaller than the difference between aerobic and hypoxic cells. No evidence for repair of potentially lethal damage was found after treatment with porfiromycin in air or in hypoxia; this is in agreement with previous findings for mitomycin C. Mitomycin C and porfiromycin therefore exhibit the toxicity to quiescent cells needed for effective use as hypoxia-directed drugs for the treatment of solid tumours.Laboratory studies and clinical trials are examining the effects of regimens combining concomitant treatment with radiation and the bioreductive alkylating agents mitomycin C or porfiromycin. This approach is based on the premise that the preferential toxicity of radiation to aerobic cells and the preferential toxicity of mitomycin C or porfiromycin to hypoxic cells might be combined to produce very effective treatment of solid tumours (Rockwell 1992). Because hypoxic cells in solid tumours are often forced into quiescence by the microenvironmental inadequacies associated with hypoxia, these combined modality regimens can be effective only if the drugs are toxic to quiescent cells, as well as to proliferating cells. Under aerobic conditions, mitomycin C is known to have similar toxicities to exponentially growing and plateau phase cultures of LoVo or EMT6 cells (Barlogie & Drewinko 1980, Rockwell 1986). It has been assumed that this finding could be generalized to porfiromycin and to hypoxic cells. However, recent studies demonstrating the complexities of the activation and metabolism of the quinone bioreductive alkylating agents

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“…Recovery from PLD has been observed in tumour cells after drug treatment both in vitro and in vivo (for review see Bertrand & Deen, 1980). It remains a possibility that if this repair can be inhibited a better clinical response following drug therapy may be achieved.…”

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confidence: 99%

Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase

Horsman¹,

Brown²,

Hirst³

et al. 1986

Br J Cancer

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Summary The effect of inhibitors of nuclear ADP-ribosyl transferase (ADPRT) on the cytotoxicity of melphalan (L-PAM) in the RIF-l tumour in vivo was investigated. A large single dose of nicotinamide (1000mgkg-') enhanced the tumour cell killing by L-PAM as measured by tumour cell survival. This enhancement was maximum when nicotinamide was administered within 1 h before injecting the L-PAM. When given at this time, the nicotinamide had a dose-modifying effect on all L-PAM doses tested, giving rise to a mean enhancement ratio (ER) of 2.2. Nicotinamide did not appear to inhibit the recovery from L-PAM induced potentially lethal damage. L-PAM (6mgkg-1) produced a transient drop in mouse body temperature. This effect was both increased and prolonged by nicotinamide. In addition the inhibitor also delayed the clearance of L-PAM from the plasma of C3H mice, such that the half-life of the chemotherapeutic agent was extended from 41 min to 143 min. The effect of combining L-PAM with nicotinamide doses below 1000mgkg-' was also investigated. The results showed that as the nicotinamide dose was decreased, the enhancement of the effects on body temperature, pharmacokinetics and white blood cell counts were reduced. However, a concomitant loss in the enhancement of tumour cell killing was also observed. Similar results were obtained using 3-aminobenzamide, a more efficient inhibitor of ADPRT.

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Factors influencing the recovery from potentially lethal damage (PLD) in mammalian cells in vitro and in vivo

Cited by 16 publications

References 67 publications

Radiation sensitivity of tumour cells stained in vitro or in vivo with the bisbenzimide fluorochrome Hoechst 33342

Radiation sensitivity of tumour cells stained in vitro or in vivo with the bisbenzimide fluorochrome Hoechst 33342

Effects of mitomycin C and porfiromycin on exponentially growing and plateau phase cultures

Changes in the response of the RIF-1 tumour to melphalan in vivo induced by inhibitors of nuclear ADP-ribosyl transferase

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